The objective of Project 1 (Function of GPIHBPI in Triglyceride Metabolism) in our Program Project Grant (PPG) is to define the function of GPIHBPI, a member of the Ly6 family of proteins, in plasma triglyceride metabolism and in the delivery of lipid nutrients to adipose tissue and muscle. This objective is closely aligned with the theme of our PPG?to understand new molecules and mechanisms underlying triglyceride delivery to parenchymal tissues, triglyceride synthesis, and adipogenesis. Over the past 5 years, our PPG team showed that GPIHBPI transports lipoprotein lipase (LPL) from the interstitial spaces (where it is secreted by adipocytes and myocytes) to its site of action within the capillary lumen. This discovery solved a longstanding mystery in plasma lipid metabolism but simultaneously highlighted other lingering mysteries within the field. For example, no one has yet defined the mechanisms by which triglyceride-rich lipoproteins (TRLs) marginate within capillaries, so that lipolysis can proceed. Other mysteries include the mechanism by which TRL-derived lipids move across endothelial cells and the precise structures governing LPL-GPIHBP1 interactions and interactions of TRLs with the LPL-GPIHBP1 complex. Also, it is unclear whether other members of the Ly6 protein family, aside from GPIHBP1, contribute to metabolism and obesity. Recently, Project 1 investigators have shown that knockouts of several Ly6 genes near Gpihbp1 are associated with protection from obesity and lower plasma lipid levels. For the next 5 years. Project 1 investigators will pursue three Specific Aims. Specific Aim 1 is to define mechanisms for the margination of TRLs in capillaries. As part of this aim, we will investigate the functional relevance of a newly discovered endothelial cell organelle, nanovilli, in TRL margination and in the transport of LPL across endothelial cells. Specific Aim 2 is to better define interactions between GPIHBP1 and LPL and to further elucidate the features of the LPL-GPIHBP1 complex required for interactions with TRLs. Specific Aim 3 is to investigate how the inactivation of a cluster of Ly6 genes (Slurpl, Slurp2, Lypd2) near Gpihbp1 affects energy balance in mice and protects against adiposity.